Veterinary Medicine - January 2008 - (Page 43)

ESSENTIAL ELEMENTS barrier.10 Pgp actively secretes absorbed substrates back into the lumen of the intestines (decreasing drug absorption), back into the lumen of the brain capillary (an active component of the blood-brain barrier), and into the bile canaliculus (active biliary secretion). The consequences of inhibiting the Pgp ef ux pump include increased oral bioavailability of Pgp substrates, increased penetration of Pgp substrates into the CNS, and decreased biliary secretion of Pgp substrates. A thorough review of Pgp substrates and inhibitors has been previously published.11 Ketoconazole’s inhibition of CYP3A12 and Pgp has been used therapeutically to decrease the dose of cyclosporine needed to achieve targeted concentrations in both dogs and cats.12,13 Ketoconazole may decrease the elimination of cisapride, vincristine, diltiazem, lidocaine, buspirone, quinidine, some benzodiazepines, and fentanyl, resulting in toxicity of the concurrently administered drug if dosages are not adjusted. Long-term phenobarbital administration increases ketoconazole metabolism and may require increased ketoconazole dosages to maintain similar ef cacy. Other adverse effects associated with ketoconazole include nausea, anorexia, and vomiting; they occur more frequently at higher dosages.1 Pruritus, alopecia, lightening of the coat, and weight loss can occur with long-term therapy.1 Slight to moderate increases in serum hepatic enzyme activities can also occur with long-term therapy, which may not be accompanied by hepatic injury. However, large increases in serum hepatic enzyme activities accompanied by elevated serum bilirubin concentrations may be indicative of hepatic injury. So routine monitoring of serum hepatic enzyme activities during long-term therapy is warranted. Cats may be more sensitive to hepatotoxicosis,1 but with the lack of pharmacokinetic studies in cats, it is unclear whether this is truly an increased sensitivity or whether the toxicosis is due to inappropriate dose recommendations. Idiosyncratic (non- Ketoconazole and terbinaﬁne Cost-effective treatment options for dermatophyte infections or yeast dermatitis and otitis in dogs and cats. Itraconazole Also an effective treatment for dermatophyte infections and yeast dermatitis, with fewer adverse effects than ketoconazole. But itraconazole may be cost-prohibitive in some cases. Fluconazole The treatment of choice for Cryptococcus species CNS infections. Fluconazole exhibits poor activity against Malassezia species and dermatophytes, so it is not routinely recommended for treating infections with these species. decreased adverse effects.16 It is available as 100-mg capsules and as a suspension (10 mg/ml). The capsules contain beads coated with itraconazole, which facilitates drug absorption from the intestines. The use of compounded itraconazole from bulk chemical is not recommended because of its low solubility and poor stability. The commercially available formulations of itraconazole are incorporated into a hydroxypropyl-betacyclodextrin carrier, so the bulk compounded formulations are not equivalent. Reformulating the capsules into smaller doses has been successful, but the beads must remain intact. The cost of itraconazole for a 44-lb dog (5 mg/kg orally once a day) is about $8/day. Potential indications Clinical uses for itraconazole include treating all of the fungal infections listed for ketoconazole, but itraconazole is preferred to ketoconazole because of its increased activity and decreased adverse effects.1 Aspergillus species is more sensitive to itraconazole than to ketoconazole, but resistance does occur.1 Itraconazole may be less active against Leishmania species compared with the other azoles.17 Itraconazole’s activity against Sporothrix schenckii is variable but itraconazole is considered the treatment of choice. In comparison to itraconazole, terbina ne, which is discussed in more detail later, has greater in vitro potency as well as demonstrated successful treatment of clinical cases in people.18,19 Voriconazole and posaconazole The newest azoles available in the United States with a primary indication for treating resistant fungal infections. However, their routine use is not recommended because of the limited information available for dogs and cats, their high cost, and the potential for inducing resistance. dose-dependent) hepatotoxicosis has also been reported in animals.1 Ketoconazole is teratogenic and not recommended for use in pregnant or lactating animals.14 Inhibition of testosterone has resulted in gynecomastia, impotence, and azoospermia in people. Cortisol production is also inhibited by ketoconazole, more so in dogs than in cats.1,15 Cataract formation has also occurred in dogs with long-term administration of ketoconazole (average duration of therapy 15 months).1 Pharmacokinetics Itraconazole is highly protein-bound (> 99%) but is well-distributed throughout the body. It accumulates in skin, liver, fat, and the adrenal medulla. Itraconazole does not reach minimum inhibitory concentrations in the cerebrospinal uid, but it has been effective in experimental models of CNS disease and in cats with Cryptococcus species CNS infections.1 In dogs, itraconazole is metabolized in part to hydroxyitraconazole, which has antifungal activity similar to ITRACONAZOLE Itraconazole is preferred to ketoconazole for most fungal infections in people because of its increased activity and VETERINARY MEDICINE January 2008 43

Table of Contents Feed for the Digital Edition of Veterinary Medicine - January 2008

Veterinary Medicine - January 2008 Contents Digital Extra Letters Toxicology Brief Idea Exchange A Challenging Case: Phimosis in a Young Adult Dog The Indications and Technique for Continuous Ambulatory Electrocardiographic Recording in Dogs A Review of Selected Systemic Antifungal Drugs for Use in Dogs and Cats CE Form Advertiser Index Marketplace/Classifieds Mind Over Miller

Veterinary Medicine - January 2008

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